Type 2 diabetes continues an unrelenting assault on health. Ample evidence implicates genetic factors in determining susceptibility although the identities of the genes and alleles have remained elusive. Genome-wide linkage efforts in diverse populations have been modestly successful in identifying regions harboring susceptibility loci, but have led to the identification of only one locus, calpain-10. Understanding the full array of genetic variation contributing to type 2 diabetes may ultimately require examination of all genes in the genome. It certainly will require comprehensive evaluation of the key genes involved in glucose homeostasis and related pathways. To this end, we have identified 500 genes most likely to influence diabetes risk. This group could represent the majority of potential diabetes genes. Evaluation of the contribution of these genes requires typing 10 to 15 SNPs in each to capture their full haplotype diversity. These studies are a necessary complement to the burgeoning genome-wide association studies (including our own) that are being performed in the context of diabetes susceptibility. Specifically, we propose: Aim 1. To determine the impact of genetic variation at 500 type 2 diabetes candidate genes on risk in 500 cases and a representative cohort of 500 Mexican Americans from Starr County, Texas;Aim 2. To test for replication of significant findings from Aim 1 in a second set of 500 cases and cohort of 500 Mexican Americans from Starr County, Texas;and Aim 3. To determine the underlying molecular variation responsible for observed associations at the pathway and gene level. DMA and phenotypes are available. We have also completed genome-wide typing using the Affymetrix GeneChip Human Mapping 100K Set on 300 of the type 2 diabetes cases and 300 cohort members that are the focus of Aim 1. In year 1 we will focus on the results from the 100K chip which provides effective coverage of 125 of the genes identified. In years 2 through 4, we will obtain genotyping through Illumina, Inc. at a rate of 125 genes per year. Genes will be examined in the context of biochemical pathways to test that the array of variation in a pathway differs between cases and the cohort. Genotypes will be posted at www.diabetesgenomics.org to permit replication and application of alternative analytic strategies. Analyses and replication and follow-up genotyping will be shared by groups at the University of Texas Health Science Center at Houston headed by Dr. Craig L. Hanis and the University of Chicago headed by Dr. Graeme I. Bell. Genotyping our extensive sample resource will permit identification of key diabetes susceptibility genes whose variation has been "permissive" to the last century's environmental changes.